"Our work explores the exciting possibility of a drug that restores connections between dopamine neurons."

Yvonne Schmitz, Ph.D.

Helping Brain Cells Talk: A Possible Path to New Treatments

In our increasingly connected world, we have come to rely heavily on our systems of communication. When telephone lines go down, or Internet connections are lost, our communities temporarily come to a halt. What if something similar were found to be happening when the human body develops Parkinson's disease (PD)? More important, what if repairing the damaged connections could help treat the disease?

These are the questions being asked by Yvonne Schmitz, Ph.D., associate research scientist at the PDF Research Center at Columbia University Medical Center,who works in the laboratory of David Sulzer, Ph.D. When Dr. Schmitz began her project five years ago, she was studying "survivor neurons" — that is, the dopamine neurons that have not yet died in Parkinson's. She knew that by the time people are diagnosed with PD, they have already lost about 30 percent of the dopamine neurons in the brain. She wanted to study the ones that remain, to understand how they keep PD at bay at first ... and why they too eventually succumb to the disease.

During her research, she stumbled across an important clue. She found that one component of the survivor neurons in PD — the axon — had become withered and weak. Axons are the long arms of cells. In order for the body to move normally, dopamine neurons "talk" to each other, by passing messages through strong and healthy axons (see box below).

In healthy dopamine neurons, the axons of the neurons reach from one area of the brain (the substantia nigra) to another (the striatum). When the axons reach the striatum, they branch out like bushes to release a chemical message, dopamine, from the tip of each branch. This means that the more branches, the better. In PD, axons are short and withered, which inhibits this process of cells sending messages or "talking" to each other.

Armed with this new knowledge, Dr. Schmitz began looking for ways to strengthen axons - in essence, to repair the phone lines, hoping that in turn, cell communication would resume. First, she and her team found that a substance called glutamate could actually strengthen and repair axons in cell cultures. This resulted in improved communication between dopamine neurons. But there was a problem: as helpful as glutamate was in fixing axons, it was also toxic. It could not realistically be developed as a treatment for people with PD.

Her team's next step was to look for alternative substances that would mimic glutamate's capacity to fix axons without being toxic. They soon found one called ACPPB. Results from initial experiments in mice showed that ACPPB enhanced axons, improved communication between dopamine neurons and improved the PD symptoms of the mice. Her team knew that years of testing would be required before it could be made available to people.

But as luck would have it, there was already a drug in development for schizophrenia — Bitopertin — which works in a very similar way to the compound their team discovered for PD. The drug is already well along in the testing process, and its safety in humans is already established. This means that if it could be proven effective in PD, the drug could come to market sooner than a compound that has only just been discovered.

Dr. Schmitz' journey with these experiments underscores the need to invest in basic science and support scientists for the long term. With the dedication of her team and the continuous support of PDF, she has been able to demonstrate that our brains function much like our communities: communication keeps things running. Imagine the possibilities if we were able to repair the phone lines and Internet connections of the brain? Dr. Schmitz says, "It's all very hopeful!"